Transgenic Stem Cells: Advancing Rare Skin Disease Treatment

Transgenic Stem Cells: Advancing Rare Skin Disease Treatment

Advancements in research for the treatment of rare skin conditions with genetically modified stem cells has recently garnered widespread attention amongst the scientific community. The novel gene therapy intervention involves the use of transgenic epidermal stem cells and was discovered by a team of researchers led by Dr. Michele de Luca, a regenerative medicine specialist from the University of Modena and Reggio Emilia. De Luca’s remarkable findings were published in Nature in November 2017 and have fostered newfound hope for individuals coping with rare skin disorders.1 Nonetheless, complications can arise with gene therapy, such as the overexpression of genes leading to tumour development.2 Despite the lack of knowledge regarding the adverse effects of the therapy on the patient, if deemed safe, this therapy could revolutionize the treatment of rare skin disorders.

In 2015, a seven-year-old from Syria named Hassan presented to a team of doctors at Children’s Hospital of Ruhr University in Bochum, Germany with junctional epidermolysis bullosa (JEB).1 JEB is the most severe form of epidermolysis bullosa (EB), accounting for 5% of EB cases.3 In Canada, EB affects 1 in 2,000 people, and approximately only 9 out of 20 people who are born with EB remain living today.3 The disease is incurable, as it is a result of a mutation in the LAMB3 gene, which is involved in skin regeneration.1 LAMB3 is one of the few genes responsible for forming laminin, an anchoring protein that assists in joining layers of the skin.4 Without the presence of the laminin protein, the layers of the skin do not adhere properly, leaving the skin thin and prone to the development of blisters, wounds, and skin loss when exposed to stressors.5 Since the skin lacks an intact barrier to protect the body from outside invaders, the patient is vulnerable to chronic infections and skin cancer, among other complications.5

Current treatment of JEB is limited, often encompassing the painful dressing and re-dressing of wounds and costing around $10,000 a year.6 After Hassan arrived at the hospital, the primary concern for physicians was to ensure his wellbeing through treatment of his infections with antibiotics, the continuous changing of dresses, and nutrition-based interventions.6 These methods were deemed ineffective, prompting the team of doctors to treat Hassan with an alloplastic tissue replacement in combination with transplanting skin from his father.6 Unfortunately, the patient rejected these attempts at skin regeneration, forcing the physicians to change to palliative care as no other options were presentable.6 The patient’s parents refused to capitulate and urged the doctors to look for other experimental therapies that could extend Hassan’s life.6 Consequently, Hassan’s physicians stumbled upon a case report published by De Luca’s team in Nature Medicine in 2006, documenting the success of utilizing genetically modified epidermal stem cells.7 The patient in the report had an identical mutation of the LAMB3 gene as demonstrated in Hassan’s genome and was treated with skin grafts made of stem cells with fully operating copies of the LAMB3 gene.8 After contacting De Luca, the patient’s parents consented to the experimental therapy and approval from the authorities was granted on the premise of compassion.5


“The study reports that Hassan is attending school regularly and is active, making him the first patient to ever be treated successfully with transgenic epidermal stem cells for large areas of the body.”

De Luca and his team of researchers performed an extraction of a 4-cm2 skin biopsy from intact epidermis located on Hassan’s inguinal region and cultured genetically modified keratinocytes with functioning copies of the LAMB3 gene.1 The process of modifying the skin cells involved retroviral factors, which consisted of an adjusted virus carrying repaired genetic material that could produce the laminin protein.8 The next steps of the therapy involved growing the cells into living pieces of tissue or skin grafts until enough was produced to cover the limbs and torso of the boy’s body. A total of 0.94 m2 of transgenic stem cells were transplanted to cover 80% of the patient’s body surface.7 Hassan underwent three different operations: the first two operations involved transplantation of the graft sheets, and the third operation was carried out to fill any additional areas of skin loss.5 A few months after the operations, biopsies of Hassan’s skin demonstrated healthy levels of the laminin protein, functional elasticity, and normal healing behaviour of the skin when exposed to bumps or bruises.1 The study reports that Hassan is attending school regularly and is active, making him the first patient to ever be treated successfully with transgenic epidermal stem cells for large areas of the body.7

The use of transgenic epidermal cells to treat skin diseases is a novel treatment and has gained coverage from the medical community. Nonetheless, when investigating the implementation of such a treatment, it is important to consider the risk of adverse side effects and the potential long-term effects on the patient. The treatment used retroviral factors, which in extremely rare occasions has been found to impair essential genes or induce the overexpression of the genes responsible for regulating tumour development.9 However, De Luca’s team accounted for this possibility through analyzing a DNA sequence from the patient’s newly modified skin and found that the insertion of genetic material occurred at locations that did not code for the genes involved in cancer formation.1,9 Moreover, it has been found that individuals diagnosed with ED have an increased likelihood of developing cancer, leading researchers to believe that the substitution of the defective epidermis cells could lower the risk of cancer.5,9 This gap of knowledge extends to concerns regarding the safety of the treatment, as while the short-term effects are known, it is unclear of whether or not the development of skin cancer is entirely unlikely.9 The treatments may not apply to all patients, as ED can be caused by a variety of gene mutations.9 Consequently, the correction of these genes using transgenic stem cells is not a definite solution and other methods of gene-editing technologies such as CRISPR-Cas9 may be appropriate in these types of circumstances.9 Lastly, this specific procedure was highly selective to a rare skin disease. For it to be pertinent towards all genetic skin disorders, the therapy must be adapted for individuals with less stringent conditions.9 Currently, the intervention seems to be the most effective in children, as their stem cells have maximal regeneration potential; however, further investigations will need to be conducted to tailor the treatment for use in adults.9


“Despite the chances of tumour development and the minimal applicability of this intervention in other conditions, it is important to highlight the forward advances in the area of rare disease treatment and the foundation in which the success of this gene therapy has now provided for future developments.”

In essence, the application of transgenic stem cells to treat rare skin disorders such as ED has been deemed to be both safe and effective in children.1 Despite the chances of tumour development and the minimal applicability of this intervention in other conditions, it is important to highlight the forward advances in the area of rare disease treatment and the foundation in which the success of this gene therapy has now provided for future developments. The implications of this breakthrough are substantial and have transcended the current field of research involving rare diseases as those who are managing with JEB may finally have a glimmer of optimism.


Works Cited:

1. Hirsch T, Rothoeft T, De Luca M, et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. 2017;551:327-332.

2. Gore ME. Adverse effects of gene therapy: Gene therapy can cause leukaemia: no shock, mild horror but a probe. Nature. 2003;10:4.

3. About Epidermolysis Bullosa. EB Awareness. https://eb-awareness.org/about-epidermolysis-bullosa/.

4. Lewis, R. Stem Cell Therapy Replaces Boy’s Entire Epidermis. Medscape. 2017; https://www.medscape.com/viewarticle/888245.

5. Williams, R. Child Receives Transgenic Skin Over Most of His Body. The Scientist. 2017; https://www.the-scientist.com/?articles.view/articleNo/50911/title/Child-Receives-Transgenic-Skin-Over-Most-of-His-Body/.

6. Servick, K. A boy with a rare disease gets new skin, thanks to gene-corrected stem cells. Science Mag. 2017; http://www.sciencemag.org/news/2017/11/boy-rare-disease-gets-new-skin-thanks-gene-corrected-stem-cells.

7. Boy is given new skin thanks to gene therapy. Science Daily. 2017; https://www.sciencedaily.com/releases/2017/11/171108151607.htm.

8. Mailvio F, Pellegrini F, De Luca M, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nature Medicine. 2006;12(12):1397-1402.

9. Aragona M, Blanpain. Gene therapy: Transgenic stem cells replace skin. Nature. 2017;551:306-307.


Cite This Article:

Rivas A., Chan G., Zhang B., Palczewski K., Lewis K., Ho J. Transgenic Stem Cells: Advancing Rare Skin Disease Treatment. Illustrated by W. Zhang. Rare Disease Review. September 2018. DOI:10.13140/RG.2.2.15572.24965.

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